Searching for unknown signs of pancreatic cancer Very little progress has been made over the last 40 years in terms of diagnosing pancreatic cancer at an early stage, therefore the prognosis for patients is often poor. We spoke to Dr Daniel Globisch about his research into biomarkers associated with pancreatic cancer, which could eventually lead to earlier diagnosis of the disease. The statistics on pancreatic cancer survival rates present a stark picture, with only about 30 percent of patients surviving the first year after an initial diagnosis. The limitations of current diagnostic techniques, which often detect pancreatic cancer relatively late, is one of the main reasons for this extremely low survival rate, as Dr Daniel Globisch explains. “There are only very rough diagnosis methods, which are based on assessing blood tests, CT scans, MRI scans or ultrasound scans. But the risk factor associated with this is very imprecise,” he says. “Another diagnostic option is a biopsy, which is highly invasive and is typically only performed at a relatively late stage of the disease, when it’s really clear from the symptoms that a patient is suffering from pancreatic cancer. However, when a patient reaches this stage with symptoms so strong that a biopsy is required, treatment options are limited.” Diagnosing pancreatic cancer This underlines the importance of finding new biomarkers for pancreatic cancer, a topic that
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Figure 1: A procedure using a chemoselective probe immobilized to magnetic beads has been developed to optimize mass spectrometric analysis of metabolites. (Garg et al. Angew. Chem. Int. Ed. 2018, 57, 13805; Conway et al. Chem. Comm. 2019, 55, 9080.)
lies at the heart of Dr Globisch’s research. Very little progress has been made in this area over the last 40 years or so, now Dr Globisch is exploring an approach based on analysis of the microbiome. “The microbiome is heavily
involved in human physiology. Disease development is evident through microbiome dysbiosis,” he explains. The microbiome itself is a topic of great interest to Dr Globisch. “With the microbiome, our bodies are populated by large communities of diverse microorganisms termed microbiota,” he continues. “This leads to the production of many unique molecules that humans cannot produce, which are then absorbed by the body. Some of these molecules have been associated with the development of different kinds of diseases.” The dysbiosis in the microbiome, which can be thought as a sort of imbalance, affects the microbial composition of the gut. A major aim in research is to identify metabolites produced by the microbiome in this context, that could eventually lead to the discovery of biomarkers for pancreatic cancer. “I see a huge potential to identify new biomarkers,” says Dr Globisch. Discovering new biomarkers is a highly complex task, but the metabolite level represents an effective starting point. “It could open up new diagnostic possibilities, with the goal of eventually
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replacing the current highly invasive biopsies,” outlines Dr Globisch. “Recent studies revealed an interaction between the microbiome and disease development. One major question remains if the microbiome dysbiosis drives the host into a disease state or the other way around?” There are many open questions here, and identifying a biomarker will provide a foundation for researchers to investigate them in greater depth. A lot of attention in research is focused on developing new tools to analyse samples, as Dr Globisch says existing techniques have some limitations. “Mass spectrometry is the most common method used in metabolomics research, where we try to identify as many molecules as possible in parallel, but certain factors limit the effectiveness of mass spectrometry,” he explains. New tools are required to obtain more information out of different types of samples (fig. 1). “In my laboratory, we have developed unique new chemical tools and work very closely with local hospitals to collect samples from patients,” says Dr Globisch. “This collaborative project brings together several experts from different areas of medicine, to help us select the samples we require for our analysis.”
will help ensure the project’s findings are highly rigorous, so providing a solid basis for Dr Globisch and his colleagues to assess whether a biomarker would be applicable to a larger population. “There may be differences in the microbiome, for example between individuals in southern and northern Europe as well as other continents,” he says. “So far, I think our results would not only be relevant for Sweden. I expect they would be more general in scope, but further work is required to validate this.”
Treatment effectiveness The primary aim of this project is to enable the earlier diagnosis of pancreatic cancer, however it could also hold wider relevance, for example in monitoring the effectiveness of treatment. Once a biomarker has been identified to help diagnose pancreatic cancer, then it could potentially also be used for prognostic purposes. “It’s important to know what the outcome of treatment is likely to be and if there is any potential for a relapse,” explains Dr Globisch. This could be a future avenue of investigation, but for the moment Dr Globisch says the priority is to find a biomarker that can be used in diagnosis. “This is a matter of
The microbiome is heavily involved in human physiology. Disease development is evident through microbiome dysbiosis. The wider goal here is to identify possible biomarkers of pancreatic cancer from these samples. While a biomarker could be a single molecule, Dr Globisch believes it is more likely to be a combination of different molecules. “A single molecule is very difficult to identify. In the future, diagnosis is more likely to be based on a metabolite pattern,” he says. Pancreatic cancer itself is a very complex disease, and it’s important to select the individual patient and control samples very carefully. “For example, we cannot compare a teenager with an elderly person, as we already know that they have a completely different microbiome. When we recruit control samples, we need to match them by age as well as other factors,” stresses Dr Globisch. “We will also compare early versus late stage to identify changes in metabolite levels.” A number of samples have been gathered so far in Sweden, and this work could eventually form the foundations of a wider study. If the initial results from the project are promising, and the biomarkers are validated, then researchers can look towards investigating a much larger cohort. “We will expand this study to analysis of patient samples from other countries,” outlines Dr Globisch. This
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identifying specific molecules, metabolites upregulated in the disease stage, it’s a bit like searching for a needle in a haystack. It’s very important that those molecules can be used for diagnostic purposes,” he continues. “There are many options here, for example certain antibody or SPR-based tests can be designed for efficient clinical analysis.” Researchers hope to improve the selectivity and analytical capabilities of the tools that have been developed in this project, which could in the future open up new possibilities to diagnose pancreatic cancer. Previously Dr Globisch discovered a biomarker for a disease called onchocerciasis, which has led to the development of a diagnostic test, now he hopes to achieve something similar with pancreatic cancer. “We developed a monoclonal antibody-based urinary lateral flow test, that will soon be tested in the field, with the goal of eventually replacing highly invasive tests,” he outlines. “That’s exactly what I want to achieve with pancreatic cancer, to identify molecules that can be used for precise diagnosis. A diagnostic test will then be developed, which could be based on fecal samples, plasma samples, or urine samples.”
Intestinal microbiota metabolism Intestinal microbiota metabolism biomarker discovery for pancreatic cancer Project Objectives
The projects are aiming at the discovery of biomarkers for pancreatic cancer and the link to gut microbiota metabolism. Biomarkers are crucial for the development of non-invasive diagnostics. To overcome limitations in the analysis of metabolites, we have developed methodologies at the interface of Chemistry and Biology for an advanced metabolomics analysis.
Project Funding
Funded by the Swedish Research Council and Science for Life Laboratory.
Project Partners
• Professor Matthias Löhr, Department for Digestive Diseases, Karolinska University Hospital • Professor Lars Engstrand, Center for Translational Microbiome Research (CTMR), Karolinska Institute
Contact Details
Project Coordinator, Dr Daniel Globisch Associate Professor Dept. Medicinal Chemistry Science for Life Laboratory Uppsala University / Sweden T: +46 (0)18-471-4287 E: Daniel.Globisch@scilifelab.uu.se W: http://www.ilk.uu.se/research-groups/ biomarker-discovery/ W: https://www.scilifelab.se/researchers/ daniel-globisch Dr Daniel Globisch
Dr Daniel Globisch received his PhD from Ludwig-Maximilians-University Munich (Germany) with Prof. Thomas Carell. For his postdoctoral studies he joined the laboratory of Prof. Kim D. Janda at The Scripps Research Institute (CA, USA). He started his independent laboratory in 2015 at Uppsala University (Sweden) and was appointed as Associate Professor in 2017.
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